<i>In silico</i> Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations

Drug repurposing is a highly popular approach to find new indications for drugs, which greatly reduces time and costs for drug design and discovery. Non-selective inhibitors of histone deacetylase (HDAC) isoforms including sirtuins (SIRTs) were showed to be effective in conditions like cancer. In this study, we identified a number of drugs molecules with potential to show pan-HDAC and pan-SIRT inhibitor activity by consensus structure-based virtual screening of FDA-approved drugs library using molecular docking to suggest drugs to be repurposed for HDAC-related indications. METHODS: The FDA-approved drugs library was optimized using MacroModel. The crystal structures of HDAC1-4, 6-8, SIRT1-3, 5, 6 were prepared and the library was docked to each structure using Glide, FRED, and AutoDock Vina/PyRx. Consensus scores were derived from the docking scores obtained from each software. Pharmacophore modeling was performed using Phase. RESULTS: According to the consensus scores, belinostat, bexarotene, and cianidanol emerged as top virtual pan-HDAC inhibitors; while alosetron, cinacalcet, and indacaterol as virtual panSIRT inhibitors. Pharmacophore hypotheses for these virtual inhibitors were also suggested through pharmacophore modelling, which were in agreement with the molecular docking models. un or ec ted pr oo f